1. Field of the Invention
The present invention relates to novel 1-hydroxy-1,1-diphosphonic acid compounds, processes for their preparation, pharmaceutical compositions containing them, and methods for their use as cytostats.
2. Description of Related Art
Hitherto known cytostatic agents for the treatment of bone tumors are non-tumor-specific and, hence, generally require very high dosages with corresponding toxic side effects, cf. H. Breidthaupt, E. Kuenzlen, (1983), "High dose methotrexate for osteosarcoma: toxicity and clinical results", Oncology 40, 85-89.
Efforts have also been made chemically to modify cytostatically active compounds in such a way that, after administration, they accumulate at the tumor sites. The concept of this research trend is based on the known fact that selected compounds belonging to certain structure types tend to accumulate in certain organs of the living organism, so that by combining an organ-specific component such as this with a cytostatically active component it would be possible to promote the transport of the cytostatically active component into the target organ. However, these efforts have not yet proved successful, at least in the majority of cases. In general, the chemically modified compounds are no longer organ-specific. This applies, for example, to the attempt to couple steroid hormones (particularly oestradiol and testosterone) with alkylating groups in order thus to attack tumors in tissues in which these hormones normally accumulate, cf. for example Journal of Medicinal Chemistry, 1979, Vol. 22, No. 2, 200-202.
In an attempt to treat liver tumors with alkylating derivatives of sulfonamides, of which the parent compound accumulates in the liver, organ specificity was thereby lost. It was only in exceptional cases which could not be predicted with any certainty that the research concept mentioned above could be put into practice more or less effectively, cf. for example Arch. Pharm. (Weinheim) 311, 184-195 (1978).
The use of nitrogen mustard derivatives is known and is standard practice for the treatment of various neoplasms. Chlorambucil, which is the approved name for 4-(4-bis-(2-chloroethyl)-amino)-phenylbutyric acid, is a substance which has been therapeutically used for some years, although it is non-specific to bone tumors. Many structurally analogous compounds have been proposed for the same purpose.
Finally, it is also known that certain polyfunctional diphosphonic acids, particularly alkane diphosphonic acids, containing a 1-hydroxy-1,1-diphosponic acid group, have the property of being absorbed by apatite and accumulate in the skeleton, cf. for example Austrian patent application 307 135 and German application 24 05 254.